Sideroblastic anemia

What every physician needs to know about sideroblastic anemia:

Sideroblastic anemias are characterized by the presence of abundant ringed sideroblasts.

Ringed sideroblasts are erythroblasts containing a perinuclear collar distribution of iron laden granules (siderotic granules) surrounding the nucleus. This distribution is due to the fact that these granules are being deposited in mitochondria which form a collar (ring) around the nucleus. In sideroblastic anemias, both the erythroblasts and circulating erythrocytes also tend to contain iron laden granules called "Pappenheimer bodies". These appear as basophilic granules on a routine peripheral blood smear.

Ringed sideroblasts and Pappenheimer bodies are both best appreciated by seeing the bone marrow aspirate for peripheral blood smear with Prussian blue.

Sideroblastic anemias ultimately arise from defects in the production of heme. Heme is a non-covalent molecular complex of reduced (ferrous-Fe++) iron with protoporphyrin IX. Defects in the production of heme can result from inadequate biosynthesis of protoporphyrin IX , failure to couple iron with protoporphyrin IX, or mitochondrial anomalies that disrupt the transport of protoporphyrin IX precursors and iron in and out of the mitochondria that normally occurs during heme biosynthesis. Consequently, there is a defect in iron utilization and inadequate production of intact hemoglobin molecules causing hypochromia.

Sideroblastic anemias are often classified among the microcytic anemias because of the defective hemoglobin synthesis. Indeed, microcytic cells are seen in most forms of sideroblastic anemias, particularly those with inherited defects or drugs toxicities. However, macrocytic cells can also be seen, probably because of associated abnormalities in erythroblastic differentiation, resulting in ineffective erythropoiesis.

Sideroblastic anemias are often dimorphic. In other words, the mean corpuscular volume (MCV) may be normal or microcytic but a broad distribution of large and small cells is seen on the peripheral smear. This is also appreciated by an elevated RDW (this is a measure of the variation in red cell diameter and size, the result is presented on the CBC slip) value on the complete blood count (CBC).

Bone marrow examination is required to confirm the diagnosis of sideroblastic anemia.

Sideroblastic anemias can be inherited or acquired.

The most commonly encountered form of acquired sideroblastic anemia is idiopathic refractory sideroblastic anemia (IRSA: Also called refractory anemia with ringed sideroblasts). This is a form of myelodysplastic syndrome, recently shown to be associated with unique mutations in the ribonucleic acid (RNA) splicing machinery.

Other acquired forms of sideroblastic anemia are due to drugs, irradiation, or, more rarely, myeloproliferative diseases. The major drugs causing sideroblastic anemia are: alcohol, isoniazid and chloramphenicol.. Anemia associated with these drugs is rarely severe, in contrast to IRSA.

The major hereditary form of sideroblastic anemia is X-linked sideroblastic anemia, an inherited defect in heme synthesis, due to mutations in the gene coding for the enzyme that is the rate limiting catalyst of the first step in heme biosynthesis: delta amino levulinic acid synthetase-2 (ALAS-2). Rarer families have been described, in which the inheritance is autosomal dominant or recessive. In some of these families, the patients in other components of the heme biosynthetic pathway have been implicated.

Ringed sideroblast, with or without significant anemia have been documented in other genetic disorders, notably:

Erythropoietic porphyria, in which significant anemia can occur

Pearson syndrome,

Zinc overload or copper deficiency

Thiamine responsive megaloblastic anemia

For unknown reasons, profound hypothermia can be associated with ring sideroblasts.

While all of these conditions can exhibit ringed sideroblasts, the vast majority of patients in whom one is likely to encounter a sideroblast anemia, will have either IRSA, a myelodysplastic syndrome occurring in the latter decades of life, or X-linked sideroblastic anemia, which often presents in childhood or early adolescence.

What features of the presentation will guide me toward possible causes and next treatment steps:

Patients with sideroblastic anemia will have anemia with a low reticulocyte count and no obvious nutritional deficiencies or underlying systemic conditions that could explain the anemia. Peripheral blood examination will frequently reveal a dimorphic population of red cells, or at least substantial anisocytosis with basophilic granules in the red cell. Suspicion of sideroblastic anemia should prompt a request for Prussian blue staining of the peripheral smear, and consideration of a bone marrow examination. Family history in younger patients will be critical to raise suspicion of an inherited form.

Patients with sideroblastic anemia will usually be iron replete, and often exhibit some indication of iron overload such as: an elevated ferritin, a high saturation of transferrin (elevated Fe/TIBC, the value that measures how much "saturated" or protein bound versus "free" iron is present in serum), and elevation in serum iron.

Not infrequently, ringed sideroblasts are identified during bone marrow examination obtained for other reasons and may or may not indicate that the anemia is truly a sideroblastic anemia. In this case, the history and clinical setting are important, notably, the possible presence of significant alcohol consumption or exposure to isoniazid. Indeed ringed sideroblasts seen in someone with acute alcohol toxicity are rarely the cause of the anemia, and will resolve when alcohol levels fall. Significant anemia in this setting is most often due to bleeding (usually gastrointestinal) and/or folate deficiency.

In patients who have sideroblastic anemias related to porphyria, Pearson syndrome, or other mitochondrial defects, the clinical presentations are usually striking, and sideroblastic anemia is an almost incidental aspect.

In cases of sideroblastic anemia that have gone undetected for prolonged periods of time, signs and symptoms of iron overload may be apparent, including bronzing of the skin, arthropathies, glucose intolerance, or even myocardial dysfunction.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

As noted above, examination of the peripheral blood smear for a dimorphic picture, an elevated red cell distribution width (RDW) value, and the presence of siderotic granules (Pappenheimer bodies) is mandatory.

Other abnormalities in the peripheral blood counts, such as an abnormal neutrophil count or platelet, might increase suspicion of a myelodysplastic syndrome associated with IRSA.

The gold standard for diagnosis of any sideroblastic anemia, is examination of the bone marrow aspirate and biopsy with Prussian blue stain for the presence of ring sideroblasts. Procurement of bone marrow tissue is an invasive procedure. Thus, one's index for suspicion should be high before obtaining bone marrow. Efforts should be made to eliminate the possibility of more common, refractory anemias, such as the anemia of chronic inflammation, by thorough history taking, physical examination, and basic laboratory studies to rule out infectious, inflammatory, or neoplastic conditions that might be affecting the bone marrow.

In adults, IRSA is most frequently diagnosed because a myelodysplastic syndrome is strongly suspected on the basis of a refractory anemia with no other likely cause.

When do you need to get more aggressive tests:

Bone marrow aspiration biopsy should be considered when all other possibilities for a hypoproliferative anemia with a dimorphic blood picture have been ruled out.

What imaging studies (if any) will be helpful?

Imaging studies are not likely to be useful for the diagnosis sideroblastic anemia.

What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?

Sideroblastic anemia almost never presents as a hematologic emergency. Initial therapy should be provided with pyridoxine (vitamin B6), 100 to 200mg/day, orally. Pyridoxine is a co-factor that stimulates steps in the heme biosynthetic pathway. A 3 month trial is used to determine if the therapy will be effective.

Pyridoxine is useful in many patients with inherited forms of sideroblastic anemia, but effective much less commonly in acquired sideroblastic anemia.

Transfusion support for patients is indicated, if the anemia is producing significant symptoms.

What other therapies are helpful for reducing complications?

Chronic transfusion therapy may be required. Because of the tendency of these patients to develop significant and rapid iron overload, iron chelation therapy should be instituted concomitantly.

The myelodysplastic syndrome associated with acquired sideroblastic anemia has been reported to be treated successfully with immunosuppressive agents, such as steroids or cyclosporin in a few patents. However, these therapies are infrequently effective and, if instituted, should be maintained for only a short trial. Bone marrow transplantation has been attempted for both severe inherited forms of sideroblastic anemia and acquired forms. The long term clinical efficacy of transplantation is still under debate.

What should you tell the patient and the family about prognosis?

Idiopathic sideroblastic anemias have a prognosis that is associated with the severity of the anemia, and the tendency of the patient to develop iron overload. In general, with aggressive management of iron overload and judicious use of blood transfusion support as well as pyridoxine, these patients should live well into adult life.

IRSA has the most favorable prognosis among the myelodysplastic syndromes, but is still a serious, life threatening illness. Survival tends to range between 3.5 to 6 years, but can be shorter or longer depending on the severity of the anemia, the success in managing iron overload, and the presence of abnormalities in neutrophils or platelets indicating, most likely, a more aggressive form of myelodysplasia. Bone marrow cytology should be performed on these patients. A normal karyotype carries the most favorable prognosis. Monosomy 7 or deletions of the long arms of chromosome 7 are associated with a worse prognosis.

“What if” scenarios.

The most common pitfall associated with the diagnosis of sideroblastic anemia, is to fail to consider the possibility in patients with refractory anemias, significant anisocytosis, and evidence of abundant iron stores with siderocytes on the peripheral smear.

The most common pitfall in management of sideroblastic anemia is failure to initiate management of iron overload with chelation, particularly when transfusion support is required.

The presence of ringed sideroblasts in patients exposed to alcohol or isoniazid is usually an associated finding, rather than the cause of significant anemia. However, some patients with isoniazid toxicity can develop significant anemia. In such patients, consider other underlying causes, especially bleeding or folate deficiency in the setting of alcohol.

Pathophysiology

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What other clinical manifestations may help me to diagnose sideroblastic anemia?

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